EFFECT OF CYTOKINES IN HOST DEFENSE AND INFLAMMATION

进行研究以确定细胞因子和其他 大鼠实验性炎症模型中的炎症介质 正常人和宿主防御异常患者 或者发炎。吸入和加热产生的皮肤水泡被用来 研究皮肤的局部炎症。它的出现的动力学 水疱液中的炎性细胞因子显示有介质出现 早期(C5a、LTB4、IL1β和IL-8)和12岁出现较晚的介质 未检测到IL-1α和IL-2的HRS(肿瘤坏死因子-α和GM-CSF)。 炎症反应异常患者皮肤水泡的研究 急性脑梗塞患者血清肿瘤坏死因子-α水平显著升高 与Wegeners肉芽肿相关的脉管炎 全身性肥大细胞增多症，以及高免疫球蛋白E和 反复感染。肿瘤坏死因子-α的升高与 疾病活动表明，针对以下目标的药物开发 这种细胞因子的调节在这些疾病中将具有特殊的优点 各州。正常水泡渗出的中性粒细胞合成大量的 IL-6、IL-8和肿瘤坏死因子-α与正常外周血的比较 中性粒细胞。正常人群和过度炎症患者的研究 提示IL-8水平与血清IL-8水平呈正相关。 渗出液中炎性中性粒细胞的数量。渗出性中性粒细胞 合成储存在非特异性隔间的IL-8 或天青颗粒，但与富含碱性磷酸酶的共洗脱 质膜组分。正常对照组给予大肠杆菌内毒素。 志愿者和患者按照长期存在的NIAID 协议。血浆肿瘤坏死因子-α、肿瘤坏死因子-α受体、白介素2水平升高 1α受体拮抗剂、IL-6、IL-8在4h内出现，G-CSF 增加6h，而IL-1α、IL-1β、IL-2、IL-3、IL-2、IL-1α、IL-1β、IL-1α、IL-2、IL-3、IL-1 4、IL-10、干扰素-γ、转化生长因子-β或C5a。有一个 内毒素后2-4小时循环E-选择素显著升高 剂量相关的给药提示E-选择素可能是 预测那些内毒素血症患者将进展为休克。 不同疾病中异常的特定介质的定义 国家对开发治疗方法很重要。在其他研究中，Long 慢性肉芽肿患者的长期监测 接受干扰素伽马治疗作为感染性预防的儿童 表明没有不良反应。在其他研究中，干扰素-伽马是 被证明有助于增强宿主对感染的防御能力 分枝杆菌，包括MAI。

Studies were performed to define the accumulation of cytokines and other mediators of inflammation in experimental models of inflammation in normal human subjects and in patients with abnormalities of host defenses or inflammation. Skin blisters created by suction and heat were used to study local inflammation in the skin. The kinetics of the appearance of inflammatory cytokines in the blister fluid revealed mediators appearing early (C5a, LTB4, IL1beta, and IL-8) and mediators appearing late at 12 hrs or later (TNF-alpha and GM-CSF) with IL-1alpha and IL-2 not detected. Studies of skin blisters in patients with abnormal inflammatory responses revealed dramatic increases in TNF-alpha in patients with acute vasculitis in association with Wegeners granulomatosis, in patients with systemic mastocytosis, and in the syndrome of hyperimmunoglobulin E and recurrent infections. Increases in TNF-alpha correlated well with disease activity suggesting that targeting drug development for modulation of this cytokine will have specific merit in these disease states. Normal blister exudate neutrophils synthesize large amounts of IL-6, IL-8, and TNF-alpha compared with control peripheral blood neutrophils. Studies of normals and patients with excessive inflammation revealed a tight linear relationship between the level of IL-8 and the number of inflammatory neutrophils in the exudate. Exudate neutrophils synthesize IL-8 which is stored in a compartment different from specific or azurophil granules, but is co-eluted with an alkaline phosphatase rich plasma membrane fraction. E. coli endotoxin was administered to normal volunteers and patients in accordance with a long standing NIAID protocol. Increased plasma levels of TNF-alpha, TNF-alpha receptor, IL- 1alpha receptor antagonist, IL-6 and IL-8 occurred within 4h and G-CSF increased by 6 h, but not changes in IL-1alpha, IL-1beta, IL-2, IL-3, IL- 4, IL-10, interferon-gamma, TGF-beta or C5a were seen. There was a striking increase in circulating E-selectin by 2-4 h after endotoxin administration which was dose related suggesting that E-selectin may be predictive of those patients with endotoxemia who will progress to shock. Definition of specific mediators that are abnormal in different disease states is important for developing therapies. In other studies the long term monitoring of patients with chronic granulomatous disease of childhood who are receiving interferon gamma as infectious prophylaxis indicated no adverse effects. In other studies interferon-gamma was shown to be useful in enhancing host defense against infection with mycobacteria including MAI.